Higher total body irradiation dose fails to improve transplant outcomes in non-Hodgkin lymphoma
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ORLANDO — Higher total body irradiation dose appeared associated with significantly higher risk for nonrelapse mortality and overall mortality among patients with non-Hodgkin lymphoma who underwent reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation, according to study results presented at TCT | Transplantation & Cellular Therapy Meetings.
In addition, the experimental 4 Gy total body irradiation dose did not reduce risk for graft failure compared with the standard 2 Gy dose.
“These data suggest 2 Gy total body irradiation is the optimal radiation dose in fludarabine/total body irradiation-based low-intensity conditioning for [patients with lymphoma],” Mehdi Hamadani, MD, professor of internal medicine at Medical College of Wisconsin, as well as director of the adult bone marrow transplantation and cellular therapy program at Froedtert Hospital, said during a presentation.
Approximately 900 patients with lymphoma underwent allogeneic HSCT in the United States in 2018, and the majority incorporated reduced-intensity conditioning platforms.
Relapse is the most common cause of therapy failure among patients with NHL who undergo reduced-intensity conditioning prior to allogeneic HSCT.
Although higher-intensity conditioning regimens have been shown to benefit patients with acute leukemia, no such benefit has been established for patients with lymphoma, according to study background.
Hamadani and colleagues aimed to determine whether increasing total body irradiation dose from 2 Gy to 4 Gy in the reduced-intensity conditioning platform would improve disease control and survival for patients with NHL.
Investigators used the Center for International Blood and Marrow Transplant Research database to evaluate outcomes of 413 adults with NHL who underwent first allogeneic HSCT using either matched related or unrelated donors between 2008 and 2017.
All patients received reduced-intensity conditioning with fludarabine plus total body irradiation at 2 Gy (n = 349) or 4 Gy (n = 64). Patients received calcineurin inhibitor-based graft-versus-host disease prophylaxis.
The 2 Gy and 4 Gy cohorts were well-balanced with regard to median age (58.7 years vs. 55.3 years), sex (male, 66.2% vs. 78.1%), donor type (matched related, 45% vs. 39.1%), lymphoma subtype, percentage of patients who were chemosensitive at allogeneic HSCT (83.5% vs. 87.5%), and median time from diagnosis to allogeneic HSCT (40.9 months vs. 32.9 months).
A significantly higher percentage of patients in the 2 Gy group had hematopoietic cell transplantation-specific comorbidity index scores of 3 or higher (43.3% vs. 21.9%; P = .003), whereas a higher percentage of patients in the 4 Gy group had Karnofsky Performance Status scores of 90 or higher (79.7% vs. 60.5%; P = .01).
OS served as the primary endpoint. Secondary endpoints included acute GVHD, chronic GVHD, nonrelapse mortality, relapse/progression and PFS.
Median follow-up was 59.3 months in the 2 Gy group and 48.5 months in the 4 Gy group.
Univariate analysis showed no significant difference between the 2 Gy and 4 Gy regimens with regard to grade 2 to grade 4 acute GVHD at 180 days (47% vs. 50%), chronic GVHD at 1 year (53% vs. 65%) or graft failure at 1 year (1.8% vs. 3.2%).
Multivariate analysis showed no significant difference between the 2 Gy and 4 Gy regimens with regard to PFS (HR = 1.09; 95% CI, 0.78-1.54). However, the 4 Gy regimen was associated with significantly shorter OS (HR = 1.51; 95% CI, 1.03-2.23) and significantly higher risk for nonrelapse mortality (HR = 1.79; 95% CI, 1.11-2.89).
Independent of conditioning regimen, complete remission at time of transplant was associated with a lower risk for progression/relapse and death after transplant.
Five-year adjusted outcomes favored the 2 Gy regimen with regard to nonrelapse mortality rate (28% vs. 47%; P = .005) and OS (51% vs. 31%; P = .03).
Primary disease was the most common cause of death in both groups, but the rate of relapse/progression at 5 years did not differ significantly between the 2 Gy and 4 Gy groups (35% vs. 29%). Results showed no significant difference in rate of relapse or graft failure at day 100. – by Mark Leiser
Reference: Hamadani M, et al. Abstract 24. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.
Disclosures: Hamadani reports research funding from, consultant roles with or speakers bureau roles with ADC Therapeutics, Celgene, Janssen, MedImmune, Merck, Otsuka Pharmaceutical, Pharmacyclics, Sanofi Genzyme and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Mazyar Shadman, MD
This is a very important study. Different doses of total body irradiation are used as part of reduced-intensity conditioning for lymphoid malignancies. This study showed you don’t get better disease control with 4 Gy but you get more toxicity, which translates to an OS disadvantage with higher-dose total body irradiation.
This study does have important implications. At our institution, for example, we have used these data to make clinical decisions. It is one example of how we can use Center for International Blood and Marrow Transplant Research data to make informed decisions based on the level of data quality from randomized trials.
There is variation in total body irradiation dose — 2 Gy, 3 Gy or 4 Gy — by institution. This study did not assess 3 Gy but, if 4 Gy is not better than 2 Gy in terms of disease control, then 3 Gy will not be better, and it still may give you more toxicity.
These findings were surprising. Fludarabine/total body irradiation is one of the least intensive conditioning regimens we use, so you would think that if you add a little bit to it, you might see benefit in terms of disease control. These data didn’t show that. There were many variables that were not controlled for, but it is the best we can get from a retrospective multicenter study.
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